Class II haplotype differentially regulates immune response in HgCl2-treated mice

One of the most striking features of exposure to low doses of mercury in mice is the high-titer haplotype-linked anti-nucleolar (ANoA) autoantibody response. Mice of H-2(s) haplotype have been high responders, while H-2(b) mice have been low. This pattern has been attributed to the class II molecule itself, but the poor response of F-1 crosses between high and low responders raised the possibility that the anti-fibrillarin specificity was actually due to a closely linked dominant negative gene. To test the role of class II explicitly, F-1 crosses between congenic B6.SJL (H-2(s)) and C57BL/6 (H-2(b)) mice with a targeted deletion of I-A(beta)(b) were generated, creating mice heterozygous for all MHC loci, but expressing only I-A(s). In comparison with B6.SJL, no diminution of ANoA titers was found, proving that I-A(s) itself was responsible for susceptibility and I-A(b) for downregulation. Unlike I-A, expression of the I-E class II molecule could not downregulate the response in an otherwise susceptible mouse. These results suggest a complicated role for class II in the regulation of a novel, environmentally induced autoimmune response. (C) 1997 Academic Press.